SCIENTIFIC PROGRAMME
SESSION I
BIOLOGY OF B-CELL
PRECURSOR ALL
SESSION II
BIOLOGY OF T-CELL ALL
SESSION III
MINIMAL RESIDUAL
DISEASE MONITORING
SESSION IV
INDIVIDUALIZED
MANAGEMENT OF ALL
SESSION V
NEW ADVANCES IN ALL
SESSION VI
CAR T-CELLS &
ALLOGENEIC HSCT
SESSION VII
FRONTLINE
INCORPORATION OF
BITES AND ADCS
SESSION VIII
T-CELL ALL AND
LYMPHOBLASTIC
LYMPHOMA
SESSION IX
PH AND PH-LIKE ALL
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
AS E-POSTERS
DISCLOSURES
DASATINIB AND NAVITOCLAX REVERSE GLUCOCORTICOID RESISTANCE IN
PRE-T-CELL RECEPTOR ACTIVATED T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA
Alistair Poll1, Yuzhe Shi2, Hayden Bell1, Edward Law1, Julie Irving1 and Frederik van Delft1
(1) Newcastle University, Newcastle upon Tyne, United Kingdom, (2) Memorial Sloan Kettering Cancer
Center, New York
Background
Outcomes in patients with T-cell Acute Lymphoblastic Leukaemia (T-ALL) have improved
markedly over the recent decades, with intensive glucocorticoid-based chemotherapy
accounting for 5-year event free survival (EFS) rates of over 80% in paediatric cases. Patrick,
et al, British Journal Haematology, 2014 Outcomes for patients refractory to or relapsing after
treatment remain extremely poor. Overcoming glucocorticoid resistance is central to
improving outcomes in these patients.
Physiological T-lymphocyte development is directed by pre T Cell Receptor (pTCR) signalling
and expression of pro-survival factors, such as BCL2 and BCL2L1. We have shown that pTCR
signalling activity is relevant in T-ALL. Dasatinib (DAS) effectively blocks the kinase LCK, which
is an instrumental signalling molecule in the pTCR pathway. Combination of DAS with
dexamethasone (DEX) impairs in vivo T-ALL expansion and results in cell death. Shi, et al,
Haematologica, 2020 Potent inhibitors of the BCL2 family have entered the clinical arena, and
demonstrated single drug activity against T-ALL.
We hypothesised that combination of DEX+DAS and BCL2 inhibition provides an effective
strategy to overcome T-ALL glucocorticoid resistance.
Methods
Cell viability assays combining DEX+DAS at a fixed ratio and BCL2 family inhibitors Venetoclax
(ABT-199) or Navitoclax (ABT-263) were performed. Cell viability was determined by resazurin
assay. T-ALL PDX, in OP9-DL1 co-culture, were exposed to DEX+DAS and BCL2 inhibitors. Cell
viability was assessed by resazurin assay, CytoQuant analysis and quantitative imaging.
Results
Both Venetoclax and Navitoclax act in an additive manner when combined with DEX+DAS in
T-ALL cell lines and primary samples. In PDX samples sensitive to DAS, we observed superior
cell kill with the addition of Navitoclax when compared to Venetoclax. Conversely, we
observed that PDX samples resistant to dasatinib are more likely to respond to Venetoclax.
The latter group is particularly enriched for Early T-cell Precursor ALLs, which rely on BCL2 for
cell survival.
Discussion
Based on these preliminary data, we suggest that T-ALL patients with activation of pTCR
signalling, as exemplified by LCK status, benefit from DEX+DAS + Navitoclax treatment to
overcome GC resistance. Other subgroups, including ETP ALL, may benefit from Venetoclax-based
treatment. We will test this treatment recommendation in preclinical models to inform
future patient management.
POSTER 19